When platelets in the blood contact subendothelial tissue after vascular endothelial cells are injured and peeled, they adhere thereto and cause an aggregation reaction. This reaction brings about thrombus formation, causing vascular disorders including thrombosis.
In the prevention and treatment of such diseases, therefore, it is important to elucidate platelet functions and consider how platelet aggregation should be suppressed.
In connection with adhesion and aggregation functions among the platelet functions, the following theory is currently held: When a stimulant, such as collagen, arachidonic acid, ADP, thrombin, serotonin or epinephrine, stimulates corresponding receptors on the platelet membrane, the glycoprotein conjugate GPIIb-IIIa on the membrane becomes capable of binding to fibrinogen in the blood via the stimulus conducting system. As a result, platelets are mutually crosslinked and aggregated.
Much still remains unknown about the actions of the above substances working as stimulants. However, it is speculated that stimuli from various stimulants including collagen activate phospholipase A2 to produce arachidonic acid from phospholipid, and the resulting arachidonic acid is metabolized into prostaglandins (PG)G2 and PGH2 by cyclooxygenase (COX), and further into thromboxane (TX)A2.
Also, the actions of the above stimulants are different. Stimuli from the stimulants, other than epinephrine and collagen, to platelets cause influx of Ca ions from outside of cells, and mobilize Ca ions from Ca storage granules, thereby raising intracellular Ca ion concentration. This causes the structural change of GPIIb-IIIa and contraction of contractile protein, arousing platelet aggregation and release reactions. With collagen, such reactions have not been observed.
In terms of the mechanism of exhibition of such platelet functions, antiplatelet drugs currently developed are classified into those acting on stimulus receptors, those acting on the stimulus conducting system (PG metabolism system inhibitors, those involved in cAMP metabolism), and those acting on GPIIb-IIIa.
GPIIb-IIIa receptor antagonists inhibit the terminal point of the aforementioned platelet reaction, and thus inhibit every platelet reaction, regardless of the cause of the platelet reaction. On the other hand, the potency of conventional GPIIb/IIIa receptor antagonists is such that its effective dose in single dose treatment is about 0.1 to 1 mg/kg by the intravenous route. Thus, this potency cannot be said to be sufficiently high.
Hence, antiplatelet drugs, which suppress platelet aggregation potently, are desired.